Journal of Perinatology (2020) 40:1506–1512 https://doi.org/10.1038/s41372-020-0642-0 ARTICLE Exchange transfusion safety and outcomes in neonatal hyperbilirubinemia 1 1 1 2 2 2 2 Mattie F. Wolf ● Julie Childers ● Keyaria D. Gray ● Caroline Chivily ● Mike Glenn ● Laila Jones ● Mini Kpa ● 2 2 1,2 3 1,2 Taylor McMannen ● Isaias Reyes ● Kanecia O. Zimmerman ● Reese H. Clark ● Rachel G. Greenberg Received: 10 October 2019 / Revised: 11 February 2020 / Accepted: 25 February 2020 / Published online: 9 March 2020 © The Author(s), under exclusive licence to Springer Nature America, Inc. 2020 Abstract Objective To characterize the prevalence of exchange transfusion (ET), clinical characteristics of infants receiving ET, and ET-associated morbidity and mortality. Study design We conducted a multicenter cohort study of infants ≥23 weeks of gestational age (GA) with hyperbilir- ubinemia who underwent ET within 30 days of birth from 1997 to 2016. We examined clinical characteristics and adverse events after ET. We used multivariable logistic regression to examine the association between clinical risk factors and death. Result A total of 1252 infants were included; 4% died within 7 days of ET and 6% died before discharge. Compared ≥ ≤ fi 1234567890();,: 1234567890();,: with infants 37 weeks of GA, infants 29 weeks of GA had greater odds of death (adjusted odds ratio [95% con dence interval] = 20.08 [7.32, 55.07]). Conclusions Infants ≤ 29 weeks of GA had greater odds of death following ET compared with term infants. These data will support clinicians in evaluating risks and prognosis for infants who require ET. Introduction hyperbilirubinemia in term infants [7, 8], there are no data on the prevalence of kernicterus in preterm survivors. Hyperbilirubinemia affects upto 85% of neonates born at Kernicterus is preventable through the use of photo- term gestation (≥37 weeks gestational age [GA]) and 80% therapy, treatment with intravenous immunoglobulins of premature newborns [1–3]. While severe hyperbilir- (IVIg), or the use of exchange transfusion (ET) to lower ubinemia (total serum bilirubin [TSB] level of >20 mg/dL serum bilirubin levels [9]. Phototherapy is an effective, [342.1 μmol/L]) occurs in <2% of term infants, it can lead to noninvasive, first-line treatment to lower the levels of permanent neurodevelopmental delay and kernicterus (i.e., unconjugated bilirubin. IVIg has some support as an adju- chronic bilirubin encephalopathy) [2]. Furthermore, though vant therapy for hyperbilirubinemia in cases of Rh hemo- preventable, kernicterus occurs in 20% of infants with TSB lytic disease, although the efficacy is controversial [10]. ET >30 mg/dL [4, 5]. The prevalence of kernicterus on autopsy is more efficient at reducing bilirubin levels and is often in preterm infants who die is thought to be around 4% [6]. used when maximal phototherapy and/or IVIg are unsuc- In addition, although small case series have described sur- cessful or when hemolysis is excessive [11, 12]; however, vivors with neurologic sequelae associated with ET has known complications including vascular accidents, cardiovascular compromise, and electrolyte and hematolo- gic derangement [13]. Furthermore, infants undergoing ET are at higher risk of requiring intubation and mechanical ventilation, both of which are associated with additional * Rachel G. Greenberg complications [14]. [email protected] The incidence of meeting or exceeding American 1 Department of Pediatrics, Duke University School of Medicine, Academy of Pediatrics thresholds for ET is low, involving Durham, NC, USA ~1.2 per 1000 live births. Nevertheless, premature infants 2 Duke Clinical Research Institute, Duke University School of have a tenfold increased risk of eventual bilirubin level Medicine, Durham, NC, USA meeting or exceeding thresholds for ET compared with term 3 Pediatrix Medical Group, Sunrise, FL, USA neonates [15]. Furthermore, the frequency of ET has Exchange transfusion safety and outcomes in neonatal hyperbilirubinemia 1507 steadily declined over time due to increased hyperbilir- ensure we did not miss important abnormalities, we eval- ubinemia screening, treating pregnant women who are uated the proportion of abnormal laboratory values on the Rh-negative with Rh-factor therapy, the increased use of day of ET in infants who were missing values within 7 days phototherapy, development of IVIg, and ET safety concerns after ET. Severe intraventricular hemorrhage (IVH) inclu- [4, 16]. Previous studies evaluating safety do not have the ded grades III and IV [28]. We defined neonatal sepsis as most current data and have been single-center evaluations or any positive blood or cerebrospinal fluid culture, including included only relatively small neonatal populations definite and probable coagulase-negative staphylococcal at [13, 14, 16–19]. In this cohort study, we sought to further any point prior to, on 1 day after, and within 7 days after ET assess and characterize the prevalence of ET use in our [29]. Necrotizing enterocolitis (NEC) included diagnosis of neonatal intensive care unit (NICU) population, as well as stage 2 or 3 by the Bell criteria [30]. Seizures were defined the safety of ET for treating hyperbilirubinemia. as documented by the provider. IVH, sepsis, NEC, and seizures were evaluated at any point prior to, on 1 day after, and within 7 days after ET. Respiratory support was col- Methods lected on the day of, 1 day after, and within 7 days after ET and included nasal cannula, continuous positive airway Study design pressure, and mechanical ventilation as documented by the provider. With the exception of laboratory abnormalities We conducted a retrospective cohort study of infants ≥ and sepsis, events were only reported after ET if they were 23 weeks of GA discharged from 1997 to 2016 from not present prior to ET. Laboratory abnormalities and Pediatrix Medical Group NICUs. For the ET population, we respiratory support were reported among infants who had included infants with hyperbilirubinemia who underwent evaluations (nonmissing data) within the time period of ET within 30 days of birth. Demographic, clinical, and interest. maternal data were extracted from a clinical data warehouse that prospectively captures data from electronic health Statistical analysis records, including daily progress notes and other doc- umentation generated by clinicians using a computer- We used descriptive statistics, including counts, percen- assisted tool [20]. The study was approved by the Duke tages, medians, and percentiles, to summarize demographic University Institutional Review Board as exempt research. characteristics and clinical data. Among the entire popula- tion of infants ≥ 23 weeks of GA, we determined the overall Variables of interest prevalence of ET in the setting of hyperbilirubinemia in the first 30 postnatal days by discharge year. Among the ET We defined ET as any infant who received ET. Known analysis population, clinical characteristics of interest partial volume ETs were excluded. Hyperbilirubinemia was included postnatal age at the time of ET and at discharge, defined as either (1) a documented diagnosis of hyperbi- the number of ETs, and receipt of IVIg prior to ET. We lirubinemia or (2) a serum bilirubin level >15 mg/dL for reported the presence of the above clinical and laboratory infants 38 weeks gestation and older, or >10 mg/dL in events of interest prior to and after ET. We reported the infants aged ≤37 weeks prior to or on the day of ET, without percentage of infants who died of any cause within 7 days evidence of an alternate diagnosis that may have justified a following ET and during hospitalization overall and by GA. requirement for ET [21, 22]. We also evaluated maximum We also reported the percentage of infants who experienced bilirubin levels for infants 1 day following ET and 7 days grade 3 or 4 IVH, sepsis, NEC, thrombocytopenia, hypo- after ET, and we noted the use of IVIg prior to ET. Small calcemia, hyperkalemia, and seizures within 7 days fol- for gestational age (SGA) status was defined based on the lowing ET by GA. We used multivariable logistic Olsen definition [23]. The number of ETs was evaluated as regression to examine the association between death before a percentage of total infants over time during the study discharge and GA, SGA status, and maximum total serum period. bilirubin. STATA 15.1 (College Station, TX) was used to Laboratory abnormalities evaluated 1 day prior to, 1 day perform statistical analyses. A p value of < 0.05 was con- after, and within 7 days after ET included: thrombocyto- sidered statistically significant. penia (platelets <100,000/µL [24, 25]), hypocalcemia (total serum calcium level < 7 mg/dL [26]), and hyperkalemia (potassium >7 mEq/L [27]). Our database did not allow us Results to distinguish timing of laboratory values, so we could not determine whether laboratory values on the day of ET Of a total 1,247,425 infants ≥ 23 weeks of GA from occurred before or after the ET. As a sensitivity analysis to 392 sites, 1252 (0.1%) underwent ET. Overall, the number 1508 M. F. Wolf et al. Table 1 Demographic characteristics of infants undergoing exchange transfusion. Characteristic N = 1252 (%) Gestational age (weeks) ≤29 159 (13) 30–34 272 (22) 35–37 338 (27) >37 483 (39) Birthweight (g) <1000 101 (8) 1000–1499 109 (9) Fig. 1 Percentage of infants undergoing ET over time. This figure 1500–2499 284 (23) displays the percentage of infants who have undergone ET from 1997 >2499 758 (61) to 2015. ET exchange transfusion. Male 687 (55) SGA 134 (11) of infants receiving ET decreased from a maximum of 0.3% Race/ethnicity to a minimum of 0.05% of all infants ≥ 23 weeks in our White 540 (45) study population over the course of the study period Black 263 (22) (Fig. 1). Among the infants who underwent ET, the median Hispanic 295 (25) (25th–75th percentile) GA and birthweight of infants Other 93 (8) receiving ET were 37 weeks (33–38 weeks) and 2789 g Inborn 856 (69) (1928–3275 g), respectively.